Lung diseases remain an important cause of morbidity and mortality in HIV+ individuals, and obstructive lung diseases such as asthma may actually be on the rise in this vulnerable population. No studies have examined prevalence of asthma or airway hyperreactivity in this population since the introduction of antiretroviral therapy, but our data suggest that asthma is increased in HIV+ individuals and may be worse in those on antiretroviral therapy. Factors unique to HIV or HIV treatment to development of HIV-associated asthma are unknown, and standard treatments of asthma may be difficult in this population, making discovery of novel treatment pathways important. The overall goal of this proposal is to examine the nature and causes of HIV-associated asthma. Based on our preliminary data, we hypothesize that HIV+ individuals have a high prevalence of asthma related to low expression and function of peroxisome proliferator-activated receptor (PPAR)-3 and adiponectin. These pathways represent potential therapeutic targets for treatment and prevention of asthma in both HIV and non-HIV-infected persons. Enrollment of a cohort of HIV+ and HIV- participants will utilize clinical, laboratory, and pulmonary function to test epidemiological hypotheses and associations of PPAR-3 and adiponectin with airway hyperreactivity, and a bronchial epithelial cell culture model will be used to test mechanistic pathways. Research aims: 1) To test the hypothesis that AHR is more common and more severe in an HIV+ cohort than in a matched non-HIV control group. 2) To test the hypothesis that airway hyperreactivity in HIV+ individuals is associated with decreased PPAR-3 and adiponectin. 3) To test the hypothesis that PPAR-3 and adiponectin decrease the inflammatory response of lung epithelial cells. Training plan: This proposal will provide the candidate with the unique opportunity to cross medical disciplines, expanding his asthma knowledge base while developing a background in HIV/AIDS, immunology, and metabolism. Through coursework and conferences, the candidate will acquire advanced training in biostatistics, epidemiology, bioinformatics, and clinical study design. The resources and experiences of mentor Dr. Morris, an expert in HIV-related chronic lung diseases, and co-mentor Dr. Wenzel, an authority in severe asthma phenotypes and translational science in studying human disease, combined with the robust research environment at the University of Pittsburgh assure the candidate's successful development to an independent researcher. PUBLIC HEALTH RELEVANCE: This proposal represents a major step in determining the impact of asthma in HIV-infected individuals. It explores potential mechanisms that are therapeutic targets for asthma which are lacking in the HIV population. Given the increasing numbers of HIV-infected subjects with prolonged exposure to HIV and antiretroviral therapy, this study will provide important information for the care and treatment of these patients.